Neuroendocrine Differentiation in Prostate Cancer: Emerging Biology, Models, and Therapies

Abstract

Although a de novo clinical presentation of small cell neuroendocrine carcinoma of the prostate is rare, a subset of patients previously diagnosed with prostate adenocarcinoma may develop neuroendocrine features in later stages of castration-resistant prostate cancer (CRPC) progression as a result of treatment resistance. Despite sharing clinical, histologic, and some molecular features with other neuroendocrine carcinomas, including small cell lung cancer, castration-resistant neuroendocrine prostate cancer (CRPC-NE) is clonally derived from prostate adenocarcinoma. CRPC-NE therefore retains early prostate cancer genomic alterations and acquires new molecular changes making them resistant to traditional CRPC therapies. This review focuses on recent advances in our understanding of CRPC-NE biology, the transdifferentiation/plasticity process, and development and characterization of relevant CRPC-NE preclinical models.

Figure 1.

Schematic view of events leading to castration-resistant neuroendocrine prostate cancer (CRPC-NE). CRPC-NE arises as a resistant mechanism to androgen receptor-targeted therapy. Over time adenocarcinoma cells undergo a selective treatment pressure, acquiring multiple genomic (e.g., RB1 and TP53) and epigenomic (e.g., DNA methylation and high EZH2) alterations together with activation of different pathways. The slicing regulator SRRM4 leads to alternative splicing and therefore to a nonfunctional variant of the neuronal repressor repressor element silencing transcription factor (REST). Cells acquire stem and neuronal characteristics associated with up-regulation of N-MYC, PEG10, and BRN2, SOX2, and SOX11. Cells start transitioning toward a mesenchymal state with up-regulation of VIM and SNAIL, drastically decreasing the expression of androgen receptor (AR) and androgen-regulated genes, such as prostate-specific antigen (PSA), and up-regulating classical neuroendocrine markers (e.g., SYP (synaptophysin), CHGA (chromogranin A), and neuron-specific enolase [NSE]). This ultimately results in increased proliferation index and mitogen signaling, including up-regulation of AURKA (Aurora Kinase A) and KI67.